UC San Diego

Spinal and Bulbar Muscular Atrophy (SBMA) is a rare neuromuscular disorder caused by a CAG repeat expansion mutation in first exon of the Androgen Receptor (AR) gene. The mutant protein is thus referred to as polyQ-AR. AR’s natural ligand, testosterone, is required for polyQ-AR to cause neuromuscular decline, thus only men are clinically affected. Historically, SBMA has been considered a motor neuron disease, but recent works from our group and others implicate skeletal muscle as a primary site of pathogenicity caused by polyQ-AR. Given that AR is a potent facilitator of skeletal muscle hypertrophy, but polyQ-AR causes progressive muscle atrophy starting in the third of fourth decade of life despite normal male development, the differences between AR and polyQ-AR molecular activity in skeletal muscle are particularly intriguing and remain elusive. Moreover, we have previously shown that polyQ-AR expression in skeletal muscle of SBMA mice is required for motor neuron pathology, which suggests a skeletal muscle-driven mechanism for motor neuron degeneration in SBMA. The neuromuscular junction (NMJ), which is a large and highly specialized synapse between motor neurons and skeletal muscle, is likely the main site of pathogenicity driving this non-cell autonomous motor neuron demise. This dissertation first provides an overview of SBMA and a published review on what is currently known about NMJ involvement in motor neuron disease. Next, I present findings in aged muscle rescued SBMA mice that develop latent phenotypes that are highly relevant to SBMA patients but have not previously been explored in animal models. In parallel, I show that motor neuron rescued SBMA mice do not experience any notable attenuation of neuromuscular decline, definitively highlighting the central role of polyQ-AR expression in skeletal muscle in driving neuromuscular decline in SBMA. Lastly, transcriptome analysis and metabolic profiling of pre-symptomatic SBMA mice provides important clues as to how polyQ-AR could initiate muscle pathology at the molecular level. Taken together, this dissertation reinforces the timely and important paradigm shift in the field toward investigating skeletal muscle, not motor neurons, as therapeutic targets in SBMA and prompts the reclassification of this repeat expansion disorder as a neuromuscular disease or even a primary myopathy